Extrachromosomal inheritance

SIGNIFICANCE: Extrachromosomal inheritance, also known as extranuclear inheritance, refers to the transmission of traits that are controlled by genes located in nonnuclear organelles such as chloroplasts and mitochondria, or in genes contained within extrachromosomal elements such as plasmids or viruses. In animals, nuclear or chromosomal traits are determined equally by both parents, but the site of nonnuclear DNA, the cytoplasm, is almost always contributed by the female parent. The understanding of this extrachromosomal inheritance is crucial, since many important traits in plants and animals—as well as mutations implicated in disease and aging—display this type of transmission. Nonnuclear traits do not demonstrate Mendelian inheritance.

Discovery of Extrachromosomal Inheritance

Carl Correns, one of the three geneticists who rediscovered Austrian botanist Gregor Mendel’s laws of inheritance in 1900, and Erwin Baur first described, independently, extrachromosomal inheritance of plastid color in 1909. However, they did not know then that they were observing the transmission patterns of organelle genes. Correns studied the inheritance of plastid color in the albomaculata strain of four-o’clock plants (Mirabilis jalapa), whereas Baur investigated garden geraniums (Pelargonium zonate). Correns observed that seedlings resembled the maternal parent regardless of the color of the male parent (uniparental-maternal inheritance). Seeds obtained from plants with three types of branches—with green leaves, white leaves, and variegated (a mixture of green and white) leaves—provided interesting results. Seeds from green-leaved branches produced only green-leaved seedlings, and seeds from white-leaved branches produced only white-leaved seedlings. However, seeds from branches with variegated leaves resulted in varying ratios of green-leaved, white-leaved, and variegated-leaved offspring. The explanation is that plastids in egg cells of the green-leaved branches and white-leaved branches were only of one type (homoplasmic or homoplastidic)—that is, normal chloroplasts in the green-leaved cells and white plastids (leukoplasts) in the white-leaved cells. The cells of the variegated branches, on the other hand, contained both chloroplasts and leukoplasts (heteroplasmic or heteroplastidic) in varying proportions. Some descendants of the heteroplastidic cells received only chloroplasts, some received only leukoplasts, and some received a mixture of the two types of plastids in varying proportions in the next generation, hence variegation.

Baur observed similar progeny from reciprocal crosses between normal green and white Pelargonium plants. Progeny in both cases were of three types: green, white, and variegated, in varying ratios. This indicated that cytoplasm was inherited from the male as well as the female parent; however, the transmission of plastids was cytoplasmic. Male transmission of plastids has also been observed in oenothera, snapdragons, beans (Phaseolus), potatoes, and rye. Rye is the only member of the grass family that exhibits both maternal and paternal inheritance of plastids.

The investigations on plastid inheritance also clearly established that in plants exhibiting uniparental-maternal inheritance, a variegated maternal parent always produces green, white, and variegated progeny in varying proportions because of its heteroplastidic nature. Crosses between green and white plants always yield green or white progeny, depending on the maternal parent, when the parental plants are homoplasmic for plastids.

Extrachromosomal Inheritance vs. Nuclear Inheritance

Extrachromosomal inheritance has been found in many plants, including barley, maize, and rice. Traits are inherited through chloroplasts, mitochondria, or plasmids (small, self-replicating structures). Inheritance of traits that are controlled by organelle genomes (plasmons) can be called nonnuclear or cytoplasmic. Among other organelles, the cytoplasm contains mitochondria in all higher organisms and mitochondria and chloroplasts in plants. Because cytoplasm is almost always totally contributed by the female parent, this type of transmission may also be called maternal or uniparental inheritance.

Most chromosomally inherited traits obey Mendel’s law of segregation, which states that a pair of alleles, or different forms of a gene, separate from each other during meiosis (the process that halves the chromosome number in formation). They also follow the law of independent assortment, in which two alleles of a gene assort and combine independently with two alleles of another gene. Such traits may be called Mendelian traits. Extrachromosomal inheritance is one of the exceptions to Mendelian inheritance. Thus, it can be called non-Mendelian inheritance. (Mendel only studied and reported on traits controlled by nuclear genes.) Mendelian heredity is characterized by regular ratios in segregating generations for qualitative trait differences and identical results from reciprocal crosses. On the contrary, non-Mendelian inheritance is characterized by a lack of regular ratio and nonidentical results from reciprocal crosses.

The mitochondria are the sites of aerobic respiration (the breaking down of organic substances to release energy in the presence of oxygen) in both plants and animals. They, like plastids, are self-replicating entities and exhibit genetic continuity. The mitochondrial genes do not exhibit the Mendelian segregation pattern either. Mitochondrial genetics began around 1950 with the discovery of “petite” mutations in baker’s yeast (Saccharomyces cerevisiae). Researchers observed that one or two out of every one thousand colonies grown on culture medium were smaller than normal colonies. The petite colonies bred true (produced only petite colonies). The petite mutants were respiration deficient under aerobic conditions. The slow growth of the petite colonies was related to the loss of a number of respiratory (cytochrome) enzymes that occur in mitochondria. These mitochondrial mutants, termed “vegetative petites,” can be induced with acriflavine and related dyes. Another type of mutation, called a “suppressive petite,” was found to be caused by defective, rapidly replicating mitochondrial DNA (mtDNA). Petite mutants that are strictly under nuclear gene control have also been reported and are called segregational petite mutants. Most respiratory enzymes are under both nuclear and mitochondrial control, which is indicative of collaboration between the two genetic systems.

Mitochondria also play a role in the programmed cell death—known as apoptosis—of eukaryotic cells, most notably cells that have accumulated potentially lethal genetic mutations. Apoptosis is also observed in ontological processes such as metamorphosis during the maturation of tadpoles into frogs or the disappearance of webbing between fingers and toes during embryonic development. In each of these examples, mitochondria undergo degeneration in the early stages.

In the fungus Neurospora, mitochondrial inheritance has been demonstrated for mutants referred to as “poky” (a slow-growth characteristic). The mutation resulted from an impaired mitochondrial function related to cytochromes involved in electron transport. The mating between poky female and normal male yields only poky progeny, but when the cross is reversed, the progeny are all normal, confirming for this mutation.

According to a 1970 study, cytoplasmic male sterility is found in about eighty plant species. The molecular basis of cytoplasmic male sterility in maize through electrophoretic separation of restriction-endonuclease-created fragments of DNA was traced to mitochondrial DNA. Cytoplasmic male sterility can be overcome by nuclear genes. The plasmids that reside in mitochondria are also important extrachromosomal DNA molecules that are especially important in antibiotic resistance. Plasmids have been found to be extremely useful in genetic engineering.

Mutator Genes

Plastome mutations can be induced by nuclear genes. A gene that increases the mutation rate of another gene is called a “mutator.” One such gene is the recessive, nuclear iojap (ij) mutation in maize. In the (ij ij) condition, it induces a plastid mutation. The name “iojap” has been derived from “Iowa” (the maize strain in which the mutation is found) and “japonica” (a type of striped variety that the mutation resembles). Once the plastid gene mutation caused by the ij gene has been initiated, the inheritance is non-Mendelian, and it no longer depends on the nuclear ij gene. As long as the iojap plants are used as female parents, the inheritance of the trait is similar to that for plastids in the albomaculata variety of four-o’clock plants.

The chm mutator gene causes plastid mutations in the plant Arabidopsis, and mutator “striata” in barley causes mutations in both plastids and mitochondria. Cases of mutator-induced mutations in the plastome have also been reported in rice and catnip.

Chloroplast and Mitochondrial DNA

Plastids contain DNA, have their own (the responsible for DNA replication), and undergo mutation. The chloroplast DNA (cpDNA) is a circular, self-replicating system approximately 140–200 kilobase pairs (kb) in size that carries genetic information, which is transcribed (from DNA to RNA) and translated (from RNA to protein) in the plastid. It replicates in a semiconservative manner—that is, an original strand of DNA is conserved and serves as the for a new strand in a manner similar to replication.

The soluble enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) is involved in photosynthetic carbon dioxide fixation. In land plants and green algae, its large subunit is a cpDNA product, while its small subunit is controlled by a nuclear gene family. Thus, the Rubisco protein, like chloroplast ribosomes, is a product of the cooperation between the nuclear and chloroplast genes. In all other algae, both the large and small subunits of Rubisco are encoded in cpDNA.

Mitochondrial DNA (mtDNA) molecules are also circular and self-replicating. Human, yeast, and higher plant mtDNAs are the major systems that have been studied. The size of mitochondrial DNA and the number of RNA or protein-encoding genes vary significantly both within and between species. Genome size among fungi ranges from 19 to 100 kb. In plants, the size of mitochondrial DNA ranges from 186 to 366 kb; in animals, from 16 to 17 kb. The human has a total of 16,569 base pairs (16.6 kb), while yeast mtDNA is five times larger than that (84 kb), and maize mtDNA is much larger than the yeast mtDNA. Every base pair of human mtDNA may be involved in coding for a mitochondrial messenger RNA (mRNA) for a protein, a mitochondrial ribosomal RNA (rRNA), or a mitochondrial transfer RNA (tRNA). It is compact, showing no intervening, noncoding base sequences between genes. It has only one major (a DNA region to which an binds and initiates transcription) on each strand. Most codons—triplets of nucleotides (bases) in messenger RNA that carry specific instructions from DNA—have the same meaning as in the universal genetic code, except for the following differences: UGA represents a “stop” signal in the universal code, but it represents tryptophan in yeast and human mtDNA; AUA represents isoleucine (universal), but methionine in human mtDNA; CUA represents leucine (universal), but threonine in yeast mtDNA; and CGG represents arginine (universal), but tryptophan in plant mtDNA.

The mtDNA carries the (plasmagene names in parentheses) for proteins, such as cytochrome oxidase subunits I (coxl), II (cox2), and III (cox3); cytochrome B (cytb); and ATPase subunits 6 (atp6), 8 (atp8), and 9 (atp9). It also contains the genetic codes for several ribosomal RNAs, such as mtrRNA 16s and 12s in mice; mtrRNA 9s, 15s, and 21s in yeast; and mtrRNA 5s, 18s, and 26s in maize. In addition, twenty-two transfer RNAs in mice, twenty-four in yeast, and three in maize are encoded in mtDNA. Most mitochondria contain between two and ten copies of the genome, all of which are identical (homoplasmy).

Chlamydomonas reinhardtii

Chlamydomonas reinhardtii is a unicellular green alga in which chloroplast and mitochondrial genes show uniparental transmission. In 1954, Ruth Sager discovered the chloroplast genetic system. Resistance to high levels of streptomycin, a trait controlled by chloroplast genes, has been shown to be transmitted uniparentally by the mt⁺ mating type parent. The mt⁻ mating type transmits the mitochondrial genes uniparentally. Mutants in chloroplasts have been identified for antibiotic and herbicide resistance. Genetic recombination is common in C. reinhardtii, which occurs in zygotes (the fused gametes of opposite sexes) when biparental cytogenes are in a (union of unlike genes) state. This is an ideal system among plants for recombination studies, since there is only one large plastid per cell. In higher plants, study of genetic recombination is difficult because of a large number of plastids in cells and a lack of genetic markers.

Mutations in mitochondria of C. reinhardtii can be induced with acriflavine or dyes. Point mutations for myxothiazol resistance mapping in the cytb gene have been isolated. The mitochondrial genome of this species of algae has been completely sequenced. It encodes five of more than twenty-five subunits of the reduced nicotinamide-adenine dinucleotide (NADH) dehydrogenase of complex I (nad1, nad2, nad4, nad5, and nad6), the COX I subunit of cytochrome oxidase (cox1), and the apocytochrome b (cob) subunit of complex III. All of these proteins have a respiratory function.

Origin of Plastid and Mitochondrial DNA

According to the endosymbiont theory, plastids and mitochondria in eukaryotes are the descendants of prokaryotic organisms that invaded primitive eukaryotes. Subsequently, they developed a symbiotic relationship and became dependent upon each other. There is much support for this theory. Researchers in 1972 showed (genetic similarity) between ribosomal RNA from photosynthetic blue-green bacteria (cyanobacteria, also erroneously called blue-green algae) and DNA from the chloroplasts of Euglena gracilis. The organization of genes is also similar to their counterpart in cyanobacteria. This provided support for the idea that chloroplasts are the descendants of cyanobacteria. Mitochondria are believed to have evolved from a variety of primitive bacteria and plastids from cyanobacteria. Molecular evidence strongly supports the endosymbiotic origin of mitochondria from both alpha purple bacteria as well as intracellular bacteria such as Rickettsia, the genus that includes the etiological agents for typhus and spotted fevers.

In 1981, Lynn Margulis summarized evidence for this theory. There are many similarities between prokaryotes and organelles: both have circular DNA and the same size ribosomes, both lack and a nuclear membrane, and both show similar response to antibiotics that inhibit protein synthesis. Both also show a primitive mode of translation that begins with formulated methionine. The discovery of promiscuous DNA (DNA segments that have been transferred between organelles or from a mitochondrial genome to the nuclear genome) in eukaryotic cells also lends support to this theory.

Impact and Applications

Genetic investigations have helped tremendously in constructing a genetic map of maize cpDNA. Important features of the map are now known, including two large, inverted repeat segments containing several rRNA and genes. Detection and quantification of mutant mtDNA are essential for the diagnosis of diseases and for providing insights into the molecular basis of pathogenesis, etiology, and ultimately the treatment of diseases. This should help enhance the knowledge of mitochondrial biogenesis. Mitochondrial dysfunction, resulting partly from mutations in mtDNA, may play a central role in organismal aging.

A number of human diseases associated with defects in mitochondrial function have been identified since their first description in 1988. Mitochondria appear to be particularly sensitive to genetic mutations—more so than nuclear DNA—perhaps due to the absence of efficient repair mechanisms for mtDNA, the lack of histones, or the accumulation of free radicals as a by-product of cell respiration by the organelle. More than 150 different types of mutations have now been identified. Large-scale deletions and tRNA point mutations(base changes) in mtDNA are associated with clinical mitochondrial encephalomyopathies. Heteroplasmy (the coexistence of more than two types of mtDNA) has provided experimental systems in which the transmission of mtDNA in animals can be studied. Numerous deleterious point mutations of mtDNA are associated with various types of human disorders involving deficiencies in the mitochondrial oxidative phosphorylation (respiration) apparatus. Leigh disease is caused by a in mtDNA. Deletions of mtDNA have been associated with diseases such as isolated ocular myopathy, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Pearson syndrome. Mitochondrial defects have also been reported in Alzheimer’s and Huntington’s diseases.

Treatment of mitochondrial diseases is primarily palliative, allowing the relief of symptoms but not eliminating the underlying defect. Genetic diagnosis of fertilized eggs provides a mechanism, albeit highly inefficient on a large scale, for allowing only the development of “healthy” embryos. Medical experiments using nonhuman primates (rhesus monkeys) have shown it is theoretically possible to replace defective mitochondria in oocytes with normal mtDNA. The process is not yet feasible in humans, as the volume of cytoplasmic material sufficient to eliminate the problem of heteroplasmy is unrealistic.

The influence of the mitochondrial genome and mitochondrial function on nuclear is poorly understood, but progress is being made toward understanding why a few genes are still sequestered in the mitochondria and developing new tools to manipulate these mitochondrial genes. The most obvious difference between mitochondrial DNA, as well as chloroplast DNA, and the DNA in free-living bacteria is in their relative size: The smallest free-living bacteria contain approximately eight hundred genes. Molecular evidence suggests that mitochondrial genes began transferring to the cell nucleus early in the evolution of endosymbiosis. The process seems to still be taking place in some plants; hundreds of genes in the Arabidopsis nucleus appear similar to those in the chloroplasts.

In 2023, scientists discovered that extrachromosomal DNA plays an important part in the development of many aggressive tumors. Their studies showed that extrachromosomal DNA acted as cancer-causing genes after separating from an individual's chromosomes. Learning to combat this process could eventually lead to revolutionary cancer treatments.

Key Terms

• genomehereditary material in the nucleus or organelle of a cell
• mitochondriasmall structures found in the cytoplasm of all higher cells that are enclosed by double membranes, produce chemical power for the cells, and harbor their own DNA
• plasmagenea self-replicating gene in a cytoplasmic organelle
• plasmonthe entire complement of genetic factors in the cytoplasm of a cell (plasmagenes or cytogenes); a plastid plasmon is referred to as a “plastome”
• plastidorganelles, including chloroplasts, that are located in the cytoplasm of plant cells and form the site for metabolic processes such as photosynthesis

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